Possible mechanisms of carcinogenesis after exposure to benzene.

We review the history of the toxicology of benzene and consider current exposure levels, the metabolism of benzene, reactions of the metabolites with biomolecules and possible mechanisms of carcinogenesis due to benzene. Epidemiological evidence indicates a relationship between exposure to benzene and the occurrence of acute non-lymphocytic leukaemia in humans. Working groups convened by IARC and other organizations have therefore judged that there is sufficient evidence for classifying benzene as a human carcinogen. Despite much research, including numerous studies in animals, the detailed mechanism of the carcinogenicity of benzene is unknown. The significant differences in the responses of rodents and humans to benzene are not understood. Benzene forms many metabolites, some of which are reactive towards biomolecules, but the metabolite(s) responsible for the induction of leukaemia is unknown. Candidate metabolites, either singly or in combination, include epoxides, oxepins, quinones and aldehydes, all of which are reactive towards proteins and DNA. Our studies on muconaldehydes and benzene oxide-oxepin are discussed in this context. The significance of DNA adduct formation in respect of human leukaemia is uncertain. The overall reactivity of benzene towards DNA has been shown to be very low in experimental animals, although dose-related reactivity of metabolites with DNA was observed. The lack of significant DNA reactivity is reflected in the lack of activity of benzene in short-term tests for genotoxicity; however, benzene causes oxidative stress, which can be detected as oxidative damage to DNA. Mechanisms other than DNA damage may play a role in benzene-related toxicity, e.g. reactions of benzene metabolites with essential enzymes such as topoisomerase II.